ST14

Gene Summary

Gene:ST14; suppression of tumorigenicity 14 (colon carcinoma)
Aliases: HAI, MTSP1, SNC19, ARCI11, MT-SP1, PRSS14, TADG15, TMPRSS14
Location:11q24-q25
Summary:The protein encoded by this gene is an epithelial-derived, integral membrane serine protease. This protease forms a complex with the Kunitz-type serine protease inhibitor, HAI-1, and is found to be activated by sphingosine 1-phosphate. This protease has been shown to cleave and activate hepatocyte growth factor/scattering factor, and urokinase plasminogen activator, which suggest the function of this protease as an epithelial membrane activator for other proteases and latent growth factors. The expression of this protease has been associated with breast, colon, prostate, and ovarian tumors, which implicates its role in cancer invasion, and metastasis. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:suppressor of tumorigenicity 14 protein
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
Show (8)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Polymerase Chain Reaction
  • Survival Rate
  • Mutation
  • Prostate Cancer
  • Serine Endopeptidases
  • Cancer Gene Expression Regulation
  • Carcinoma
  • siRNA
  • Xenopus
  • MicroRNAs
  • Chromosome 11
  • Transcription Factors
  • Cancer DNA
  • Ovarian Cancer
  • Neoplasm Metastasis
  • Western Blotting
  • Signal Transduction
  • Pancreatic Cancer
  • Cell Adhesion
  • Tumor Markers
  • Mammary Neoplasms, Animal
  • Cell Movement
  • Proteinase Inhibitory Proteins, Secretory
  • Gene Expression Profiling
  • Membrane Glycoproteins
  • Disease Progression
  • ras Proteins
  • RTPCR
  • FISH
  • Colorectal Cancer
  • Cell Proliferation
  • Enzymologic Gene Expression Regulation
  • Immunohistochemistry
  • Breast Cancer
  • Up-Regulation
  • Oligonucleotide Array Sequence Analysis
  • Trypsin
  • Gene Expression
  • Transfection
  • Neoplasm Invasiveness
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ST14 (cancer-related)

Zhang DG, Zheng JN, Pei DS
P53/microRNA-34-induced metabolic regulation: new opportunities in anticancer therapy.
Mol Cancer. 2014; 13:115 [PubMed] Free Access to Full Article Related Publications
MicroRNA-34 (miR-34) is directly regulated by p53, and its potential tumor suppressive roles have been studied extensively. As a p53-induced microRNA, miR-34 functions as a tumor suppressor by playing a role in cell cycle arrest, apoptosis and metabolic regulation. Among these p53/miR-34 associated processes, apoptosis and cell cycle arrest are known as essential for p53/miR-34-mediated tumor suppression. P53-mediated metabolic processes have been shown to play pivotal roles in cancer cell biology. Recent studies have also identified several miR-34 targets involved in p53/miR-34-induced metabolic regulation. However, correlations among these metabolic targets remain to be fully elucidated. In this review, we summarize the current progress in the field of metabolic regulation by the p53/miR-34 axis and propose future directions for the development of metabolic approaches in anticancer therapy.

Eshhar Z, Waks T, Gross G
The emergence of T-bodies/CAR T cells.
Cancer J. 2014 Mar-Apr; 20(2):123-6 [PubMed] Related Publications
The nickname "T-body" is used to denote a T cell expressing an antigen-specific or antibody-based chimeric receptor that combines antibody specificity with T-cell effector or regulatory function. Initially, we designed and constructed chimeric antibody-based receptors and expressed them in T cells to study the role of major histocompatibility complex in triggering T-cell activation. To this end, we replaced both variable domains (Vα and Vβ of the native T-cell receptor chains) with antibody-derived VH and VL sequences. After transfection into T cells, the 2 chimeric chains paired, associated with the CD3 complex, and endowed transfectants with non-major histocompatibility complex-restricted antibody type specificity. In subsequent studies, we developed next generation of chimeric antibody-based receptors by fusing an antibody single-chain variable fragment to T-cell activation motifs. This modular configuration simplified gene transfer, avoided mixed pairing with endogenous T-cell receptor chains, and enabled simultaneous insertion of various domains as costimulatory moieties to generate T-bodies with efficient antitumor reactivity.

Hu C, Jiang N, Wang G, et al.
Expression of hepatocyte growth factor activator inhibitor-1 (HAI-1) gene in prostate cancer: clinical and biological significance.
J BUON. 2014 Jan-Mar; 19(1):215-20 [PubMed] Related Publications
PURPOSE: Hepatocyte growth factor activator inhibitor type-1 (HAI-1) is an integral-membrane proteinase inhibitor. Some studies have shown that HAI-1 as a matriptase inhibitor that plays a significant role in regulating cancer progression and metastasis. In this study, we attempted to clarify whether the levels of HAI-1 could be a useful marker in patients with prostate cancer (Pca).
METHODS: HAI-1 protein was evaluated by immunohistochemistry (IHC) and HAI-1 mRNA was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) in 48 patients with Pca and 20 patients with benign prostate hyperplasia (BPH). The association between HAI-1 and clinicopathological features and survival were analyzed.
RESULTS: A high level of HAI-1 protein and mRNA expression was detected in BPH compared to Pca specimens. The HAI-1 expression inversely correlated with Gleason score and pathological stage (p<0.05). It was significantly stronger in N0M0 tumors than in N+ or M+ tumors (p<0.05). Furthermore, low HAI-1 expression was a significant predictor for poor prognosis when compared with high HAI-1 expression (disease-free survival/DFS rate, p=0.0487; overall survival/ OS rate; p=0.0492).
CONCLUSION: The results of the present study identified HAI-1 as a favorable prognostic marker for Pca and may indicate that HAI-1 could be a therapeutic target for the treatment of this malignancy.

Weng YR, Yu YN, Ren LL, et al.
Role of C9orf140 in the promotion of colorectal cancer progression and mechanisms of its upregulation via activation of STAT5, β-catenin and EZH2.
Carcinogenesis. 2014; 35(6):1389-98 [PubMed] Related Publications
C9orf140 is a newly identified and characterized gene which is associated with cell proliferation and tumorigenicity. Expression of C9orf140 is upregulated in human gastric cancer and colorectal cancer (CRC); however, little is known about its role in CRC progression. We have investigated the clinical significance, biological effects and mechanisms of C9orf140 signaling. We found that the expression of C9orf140 is dramatically increased in a subset of CRC and correlates significantly with vascular invasion and lymph node metastasis. Our finding showed that knockdown of C9orf140 significantly reduced cell proliferation and invasion in vitro and dramatically increased overall survival and decreased lung metastasis in vivo. Conversely, overexpression of C9orf140 significantly increased lung metastasis and shortened overall survival when compared with control tumors. C9orf140-induced CRC cell invasion may depend on promoting the epithelial-mesenchymal transition progression. STAT5 may directly interact with the enhancer of zeste homolog 2 (EZH2) and β-catenin to enhance C9orf140 gene transactivation. Furthermore, C9orf140 may participate in cell invasion which is induced by STAT5, EZH2 or β-catenin activation. We describe the role of C9orf140 in CRC progression and find that C9orf140 overexpression may be regulated by STAT5, EZH2 and β-catenin interaction.

Liang J, Zhang X, Xie S, et al.
Ubiquitin-specific protease 22: a novel molecular biomarker in glioma prognosis and therapeutics.
Med Oncol. 2014; 31(4):899 [PubMed] Related Publications
Ubiquitin-specific protease 22 (USP22) exhibits an important function in tumor progression and oncogenesis. The aim of this study was to investigate the role of USP22 and the association with its potential targets in patients with glioma. To our knowledge, this is the first study that determines the relationship between USP22 expression and clinicopathological significance in glioma. In our study, USP22 protein levels were detected by Western blot analysis. The protein levels of USP22 in glioma tissues were significantly higher than non-tumors. The immunohistochemistry results showed that USP22 protein was overexpressed in glioma tissues compared with non-tumors. The higher the grade of gliomas, the higher the level of USP22 expression. Further, the results of Kaplan-Meier analysis indicated that patients with high USP22 expression had significantly worse overall survival than patients with low expression of USP22. It suggested that USP22 overexpression may be associated with poor prognosis in patients with glioma. It may represent a novel prognostic biomarker or a target for improving the treatment efficiency of patients with glioma.

Miller GS, Zoratti GL, Murray AS, et al.
HATL5: a cell surface serine protease differentially expressed in epithelial cancers.
PLoS One. 2014; 9(2):e87675 [PubMed] Free Access to Full Article Related Publications
Over the last two decades, cell surface proteases belonging to the type II transmembrane serine protease (TTSP) family have emerged as important enzymes in the mammalian degradome, playing critical roles in epithelial biology, regulation of metabolic homeostasis, and cancer. Human airway trypsin-like protease 5 (HATL5) is one of the few family members that remains uncharacterized. Here we demonstrate that HATL5 is a catalytically active serine protease that is inhibited by the two Kunitz type serine protease inhibitors, hepatocyte growth factor activator inhibitor (HAI)-1 and 2, as well as by serpinA1. Full-length HATL5 is localized on the cell surface of cultured mammalian cells as demonstrated by confocal microscopy. HATL5 displays a relatively restricted tissue expression profile, with both transcript and protein present in the cervix, esophagus, and oral cavity. Immunohistochemical analysis revealed an expression pattern where HATL5 is localized on the cell surface of differentiated epithelial cells in the stratified squamous epithelia of all three of these tissues. Interestingly, HATL5 is significantly decreased in cervical, esophageal, and head and neck carcinomas as compared to normal tissue. Analysis of cervical and esophageal cancer tissue arrays demonstrated that the squamous epithelial cells lose their expression of HATL5 protein upon malignant transformation.

Organ SL, Hai J, Radulovich N, et al.
p120RasGAP is a mediator of rho pathway activation and tumorigenicity in the DLD1 colorectal cancer cell line.
PLoS One. 2014; 9(1):e86103 [PubMed] Free Access to Full Article Related Publications
KRAS is mutated in ∼40% of colorectal cancer (CRC), and there are limited effective treatments for advanced KRAS mutant CRC. Therefore, it is crucial that downstream mediators of oncogenic KRAS continue to be studied. We identified p190RhoGAP as being phosphorylated in the DLD1 CRC cell line, which expresses a heterozygous KRAS G13D allele, and not in DKO4 in which the mutant allele has been deleted by somatic recombination. We found that a ubiquitous binding partner of p190RhoGAP, p120RasGAP (RasGAP), is expressed in much lower levels in DKO4 cells compared to DLD1, and this expression is regulated by KRAS. Rescue of RasGAP expression in DKO4 rescued Rho pathway activation and partially rescued tumorigenicity in DKO4 cells, indicating that the combination of mutant KRAS and RasGAP expression is crucial to these phenotypes. We conclude that RasGAP is an important effector of mutant KRAS in CRC.

Zhang Y, Jin B, Shao M, et al.
Monitoring of carcinoembryonic antigen levels is predictive of EGFR mutations and efficacy of EGFR-TKI in patients with lung adenocarcinoma.
Tumour Biol. 2014; 35(5):4921-8 [PubMed] Related Publications
For the detection of epidermal growth factor receptor (EGFR) mutations, tumor tissues may not always be available. Not all the patients harboring EGFR mutation have a clinical response after the treatment of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI). EGFR mutations were detected in 70 cases of newly diagnosed non-smoking adenocarcinoma, and patients harboring EGFR mutations received EGFR-TKI treatment. The EGFR mutation status of these patients' blood was analyzed by amplification refractory mutation system (ARMS). The patients' carcinoembryonic antigen (CEA) levels were tested on the third, seventh, 15(th), and 30th days after EGFR-TKI treatment. Forty-four cases were found with EGFR mutations. EGFR mutation rate of CEA high-level group was significantly higher than low-level group (70.8% vs. 40.9%, P = 0.017). Multivariate analysis showed that high-level CEA is independently associated with EGFR gene mutation (P = 0.020, OR = 3.508, 95%CI, 1.223-10.059). The sensitivity of high CEA level and ARMS to predict EGFR mutation were 79.1% and 51.2%. We divided the patients who received EGFR-TKI treatment into three groups by the variation types of CEA. Univariate analysis showed that patients in descending type group have longer progression-free survival (P = 0.001, HR 6.981, 95%CI, 2.534-19.237). Multivariate Cox proportional hazards model analyses shows the same result (P = 0.001, HR 9.82, 95%CI, 3.322-26.031). In conditions of the current technique, using high CEA level to predict EGFR mutations seems to be more sensitive than using EGFR mutations in plasma. The variation types of CEA level could help us to predict the efficacy of EGFR-TKI in patients harboring EGFR mutation within only 1 month of tyrosine kinase inhibitor therapy.

Jiao X, Lu HJ, Zhai MM, et al.
Overexpression of kallikrein gene 10 is a biomarker for predicting poor prognosis in gastric cancer.
World J Gastroenterol. 2013; 19(48):9425-31 [PubMed] Free Access to Full Article Related Publications
AIM: To analyze the expression of kallikrein gene 10 (KLK10) in gastric cancer and to determine whether KLK10 has independent prognostic value in gastric cancer.
METHODS: We studied KLK10 expression in 80 histologically confirmed gastric cancer samples using real-time quantitative reverse transcription-PCR and hK10 expression using immunohistochemistry. Correlations with clinicopathological variables (lymph node metastasis, depth of invasion and histology) and with outcomes (disease-free survival and overall survival) during a median follow-up period of 31 mo were assessed. Gastric cancer tissues were then classified as KLK10 positive or negative.
RESULTS: KLK10 was found to be highly expressed in 57/80 (70%) of gastric cancer samples, while its expression was very low in normal gastric tissues. Positive relationships between KLK10 expression and lymph node metastasis (P = 0.048), depth of invasion (P = 0.034) and histology (P = 0.015) were observed. Univariate survival analysis revealed that gastric cancer patients with positive KLK10 expression had an increased risk for relapse/metastasis and death (P = 0.005 and 0.002, respectively). Cox multivariate analysis indicated that KLK10 was an independent prognostic indicator of disease-free survival and overall survival in patients with gastric cancer.
CONCLUSION: KLK10 expression is an independent biomarker of unfavorable prognosis in patients with gastric cancer.

Xue Q, Sun K, Deng HJ, et al.
Anti-miRNA-221 sensitizes human colorectal carcinoma cells to radiation by upregulating PTEN.
World J Gastroenterol. 2013; 19(48):9307-17 [PubMed] Free Access to Full Article Related Publications
AIM: To investigate the regulative effect of miRNA (miR)-221 on colorectal carcinoma (CRC) cell radiosensitivity and the underlying mechanisms.
METHODS: A human CRC-derived cell line was cultured conventionally and exposed to different doses of X-rays (0, 2, 4, 6 and 8 Gy). The total RNA and protein of the cells were extracted 24 h after irradiation, and the alteration of miR-221 and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene mRNA expression was detected by real-time reverse transcriptase polymerase chain reaction (PCR). The protein alteration of PTEN in the cells was detected by Western blotting. Caco2 cells were pretreated with or without anti-PTEN-siRNA prior to the addition of pre-miR-221 or anti-miR-221 using Lipofectamine 2000. Colony formation assay and flow cytometry analysis were used to measure the surviving cell fraction and the sensitizing enhancement ratio after irradiation. Additionally, PTEN 3'-untranslated region fragment was PCR amplified and inserted into a luciferase reporter plasmid. The luciferase reporter plasmid construct was then transfected into CRC cells together with pre-miR-221 or anti-miR-221, and the luciferase activity in the transfected cells was detected.
RESULTS: The X-ray radiation dose had a significant effect on the expression of miR-221 and PTEN protein in human Caco2 cells in a dose-dependent manner. The miR-221 expression level improved gradually with the increase in irradiation dose, while the PTEN protein expression level reduced gradually. miR-221 expression was significantly reduced in the anti-miR-221 group compared with the pre-miR-221 and negative control groups (P < 0.01). Anti-miR-221 upregulated expression of PTEN protein and enhanced the radiosensitivity of Caco2 cells (P < 0.01). Moreover, the inhibitory effect was dramatically abolished by pretreatment with anti-PTEN-siRNA, suggesting that the enhancement of radiosensitivity was indeed mediated by PTEN. A significant increase of luciferase activity was detected in CRC cells that were cotransfected with the luciferase reporter plasmid construct and anti-miR-221 (P < 0.01).
CONCLUSION: Anti-miR-221 can enhance the radiosensitivity of CRC cells by upregulating PTEN.

Meng Q, Zhi T, Chao Y, et al.
Bex2 controls proliferation of human glioblastoma cells through NF-κB signaling pathway.
J Mol Neurosci. 2014; 53(2):262-70 [PubMed] Related Publications
Glioblastoma is the most common and fatal human brain malignancy in adults with highly proliferative capacity. Despite advances in surgery and adjuvant therapy, the median survival of patients has changed little over recent decades. Identifying molecules critical for glioma development is significant for devising effective targeted therapy. We previously reported that Bex2, a member of the brain expressed X-linked gene family, promoted the progression of glioma by promoting cell proliferation. In the present study, we investigated the main mechanism of Bex2 promoting the proliferation of glioblastoma cells. We found that Bex2 downregulation inhibited glioma cell proliferation and the expression of NF-κB p65, but Bex2 overexpression promoted them. Similarly, the proliferation of glioma cells was inhibited by p65 downregulation but increased by p65 overexpression. In addition, Bex2 overexpression-induced cell proliferation was abolished by p65 downregulation. Furthermore, Bex2 with nuclear localization signal deleted no longer promoted p65 expression. In conclusion, this study demonstrates that Bex2 promotes proliferation of human glioblastoma cells via NF-κB signaling pathway and Bex2 nuclear location is critical for p65 expression.

Chen L, Li WF, Wang HX, et al.
Curcumin cytotoxicity is enhanced by PTEN disruption in colorectal cancer cells.
World J Gastroenterol. 2013; 19(40):6814-24 [PubMed] Free Access to Full Article Related Publications
AIM: To investigate the effects of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) deficiency on the cytotoxicity of chemotherapeutic agents toward colorectal cancer cells.
METHODS: PTEN-deficient colorectal cancer (CRC) cells were generated by human somatic cell gene targeting using the adeno-associated virus system. The cytotoxic effects of compounds including curcumin, 5-fluorouracil (5-FU), dihydroartemisinin (DHA), irinotecan (CPT-11) and oxaliplatin (OXA) on cancer cells were determined using the MTT assay. Enhanced cytotoxicity of curcumin in PTEN-deficient CRC cells was observed, and this was confirmed using clonogenic assays. Apoptosis and cell cycle progression were analyzed by flow cytometry. Levels of apoptosis and cell cycle-related proteins were examined by Western blotting.
RESULTS: We developed an isogenic set of CRC cell lines that differed only in their PTEN status. Using this set of cell lines, we found that disruption of the PTEN gene had no effect on the sensitivity of CRC cells to 5-FU, CPT-11, DHA, or OXA, whereas PTEN disruption increased the sensitivity of CRC cells to curcumin. Loss of PTEN did not alter the curcumin-induced apoptosis in CRC cells. However, PTEN deficiency led to an altered pattern of curcumin-mediated cell cycle arrest. In HCT116 PTEN (+/+) cells, curcumin caused a G2/M phase arrest, whereas it caused a G0/G1 phase arrest in HCT116 PTEN (-/-) cells. Levels of cell cycle-related proteins were consistent with these respective patterns of cell cycle arrest.
CONCLUSION: Curcumin shows enhanced cytotoxicity toward PTEN-deficient cancer cells, suggesting that it might be a potential chemotherapeutic agent for cancers harboring PTEN mutations.

Hai B, Qin L, Yang Z, et al.
Transient activation of hedgehog pathway rescued irradiation-induced hyposalivation by preserving salivary stem/progenitor cells and parasympathetic innervation.
Clin Cancer Res. 2014; 20(1):140-50 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To examine the effects and mechanisms of transient activation of the Hedgehog pathway on rescuing radiotherapy-induced hyposalivation in survivors of head and neck cancer.
EXPERIMENTAL DESIGN: Mouse salivary glands and cultured human salivary epithelial cells were irradiated by a single 15-Gy dose. The Hedgehog pathway was transiently activated in mouse salivary glands, by briefly overexpressing the Sonic hedgehog (Shh) transgene or administrating smoothened agonist, and in human salivary epithelial cells, by infecting with adenovirus encoding Gli1. The activity of Hedgehog signaling was examined by the expression of the Ptch1-lacZ reporter and endogenous Hedgehog target genes. The salivary flow rate was measured following pilocarpine stimulation. Salivary stem/progenitor cells (SSPC), parasympathetic innervation, and expression of related genes were examined by flow cytometry, salisphere assay, immunohistochemistry, quantitative reverse transcription PCR, Western blotting, and ELISA.
RESULTS: Irradiation does not activate Hedgehog signaling in mouse salivary glands. Transient Shh overexpression activated the Hedgehog pathway in ductal epithelia and, after irradiation, rescued salivary function in male mice, which is related with preservation of functional SSPCs and parasympathetic innervation. The preservation of SSPCs was likely mediated by the rescue of signaling activities of the Bmi1 and Chrm1-HB-EGF pathways. The preservation of parasympathetic innervation was associated with the rescue of the expression of neurotrophic factors such as Bdnf and Nrtn. The expression of genes related with maintenance of SSPCs and parasympathetic innervation in female salivary glands and cultured human salivary epithelial cells was similarly affected by irradiation and transient Hedgehog activation.
CONCLUSIONS: These findings suggest that transient activation of the Hedgehog pathway has the potential to restore salivary gland function after irradiation-induced dysfunction.

Tsai CH, Teng CH, Tu YT, et al.
HAI-2 suppresses the invasive growth and metastasis of prostate cancer through regulation of matriptase.
Oncogene. 2014; 33(38):4643-52 [PubMed] Free Access to Full Article Related Publications
Dysregulation of cell surface proteolysis has been strongly implicated in tumorigenicity and metastasis. In this study, we delineated the role of hepatocyte growth factor activator inhibitor-2 (HAI-2) in prostate cancer (PCa) cell migration, invasion, tumorigenicity and metastasis using a human PCa progression model (103E, N1, and N2 cells) and xenograft models. N1 and N2 cells were established through serial intraprostatic propagation of 103E human PCa cells and isolation of the metastatic cells from nearby lymph nodes. The invasion capability of these cells was revealed to gradually increase throughout the serial isolations (103E

Liu XJ, Chen ZF, Li HL, et al.
Interaction between cyclooxygenase-2, Snail, and E-cadherin in gastric cancer cells.
World J Gastroenterol. 2013; 19(37):6265-71 [PubMed] Free Access to Full Article Related Publications
AIM: To investigate the mechanisms of how cyclooxygenase-2 (COX-2) regulates E-cadherin in gastric cancer cells.
METHODS: COX-2 expression in human gastric cancer cell lines SGC-7901, BGC-823, MGC-803 and AGS were measured at the mRNA and protein level. COX-2 rich cell line SGC-7901 was chosen for subsequent experiments. siRNA mediated gene knockdown was used to investigate the impact of COX-2 on nuclear factor-κB (NF-κB), Snail, and E-cadherin in gastric cancer cells. Gene expression was determined by Western blot and real-time polymerase chain reaction. To analyze whether NF-κB inhibition could interrupt the modulatory effect of COX-2 or prostaglandin E2 (PGE2) on E-cadherin, gastric cancer cells were treated with celecoxib or PGE2, in the presence of NF-κB specific siRNA.
RESULTS: Highest expression level of COX-2 was found in SGC-7901 cells, both at mRNA and protein levels. siRNA mediated down-regulation of COX-2 led to a reduced expression of NF-κB and Snail, but an increased expression of E-cadherin in SGC-7901 cells. siRNA mediated down-regulation of NF-κB also led to a reduced expression of E-cadherin and Snail in SGC-7901 cells. However, COX-2 expression did not alter after cells were treated with NF-κB specific siRNA in SGC-7901 cells. Treatment of SGC-7901 cells with celecoxib led to a reduced expression of Snail but an increased expression of E-cadherin. In contrast, treatment of SGC-7901 cells with PGE2 led to an increased Snail and a decreased E-cadherin. However, siRNA-mediated knockdown of NF-κB partially abolished the effect of celecoxib and PGE2 on the regulation of E-cadherin and Snail in SGC-7901 cells.
CONCLUSION: COX-2 likely functions upstream of NF-κB and regulates the expression of E-cadherin via NF-κB/Snail signaling pathway in gastric cancer cells.

Rong G, Kang H, Wang Y, et al.
Candidate markers that associate with chemotherapy resistance in breast cancer through the study on Taxotere-induced damage to tumor microenvironment and gene expression profiling of carcinoma-associated fibroblasts (CAFs).
PLoS One. 2013; 8(8):e70960 [PubMed] Free Access to Full Article Related Publications
Recently, emerging evidence has suggested that carcinoma-associated fibroblasts (CAFs) could contribute to chemotherapy resistances in breast cancer treatment. The aim of this study is to compare the gene expression profiling of CAFs before and after chemotherapy and pick up candidate genes that might associate with chemotherapy resistance and could be used as predictors of treatment response. CAFs were cultured from surgically resected primary breast cancers and identified with immunohistochemistry (IHC) and Flow cytometry (FCM). MDA-MB-231 cells were cultured as the breast cancer cell line. Cell adhesion assay, invasion assay, and proliferation assay (MTT) were performed to compare the function of MDA-MB-231 cells co-cultured with CAFs and MDA-MB-231 cells without co-culture, after chemotherapy. Totally 6 pairs of CAFs were prepared for microarray analysis. Each pair of CAFs were obtained from the same patient and classified into two groups. One group was treated with Taxotere (regarded as after chemotherapy) while the other group was not processed with Taxotere (regarded as before chemotherapy). According to our study, the primary-cultured CAFs exhibited characteristic phenotype. After chemotherapy, MDA-MB-231 cells co-cultured with CAFs displayed increasing adhesion, invasiveness and proliferation abilities, compared with MDA-MB-231 cells without CAFs. Moreover, 35 differentially expressed genes (absolute fold change >2) were identified between CAFs after chemotherapy and before chemotherapy, including 17 up-regulated genes and 18 down-regulated genes. CXCL2, MMP1, IL8, RARRES1, FGF1, and CXCR7 were picked up as the candidate markers, of which the differential expression in CAFs before and after chemotherapy was confirmed. The results indicate the changes of gene expression in CAFs induced by Taxotere treatment and propose the candidate markers that possibly associate with chemotherapy resistance in breast cancer.

Fan YC, Mei PJ, Chen C, et al.
MiR-29c inhibits glioma cell proliferation, migration, invasion and angiogenesis.
J Neurooncol. 2013; 115(2):179-88 [PubMed] Related Publications
Previous studies reported that miR-29c is significantly downregulated in several tumors. However, little is known about the effect and molecular mechanisms of action of miR-29c in human glioma. Using quantitative RT-PCR, we demonstrated that miR-29c was significantly downregulated in glioma cell lines and human primary glioma tissues, compared to normal human astrocytes and matched non-tumor associated tissues (P < 0.05, χ(2) test). Overexpression of miR-29c dramatically reduced the proliferation and caused cessation of cell cycle. The reduced cell proliferation is due to G1 phase arrest as cyclin D1 and cyclin E are diminished whereas p27 and p21 are upregulated. We further demonstrated that miR-29c overexpression suppressed the glioma cell migration and invasion abilities by targeting MMP-2. In addition, we also found that overexpression of miR-29c sharply inhibited angiogenesis, which correlated with down-regulation of VEGF. The data indicate that miR-29c may be a tumor suppressor involved in the progression of glioma.

Wolford CC, McConoughey SJ, Jalgaonkar SP, et al.
Transcription factor ATF3 links host adaptive response to breast cancer metastasis.
J Clin Invest. 2013; 123(7):2893-906 [PubMed] Free Access to Full Article Related Publications
Host response to cancer signals has emerged as a key factor in cancer development; however, the underlying molecular mechanism is not well understood. In this report, we demonstrate that activating transcription factor 3 (ATF3), a hub of the cellular adaptive response network, plays an important role in host cells to enhance breast cancer metastasis. Immunohistochemical analysis of patient tumor samples revealed that expression of ATF3 in stromal mononuclear cells, but not cancer epithelial cells, is correlated with worse clinical outcomes and is an independent predictor for breast cancer death. This finding was corroborated by data from mouse models showing less efficient breast cancer metastasis in Atf3-deficient mice than in WT mice. Further, mice with myeloid cell-selective KO of Atf3 showed fewer lung metastases, indicating that host ATF3 facilitates metastasis, at least in part, by its function in macrophage/myeloid cells. Gene profiling analyses of macrophages from mouse tumors identified an ATF3-regulated gene signature that could distinguish human tumor stroma from distant stroma and could predict clinical outcomes, lending credence to our mouse models. In conclusion, we identified ATF3 as a regulator in myeloid cells that enhances breast cancer metastasis and has predictive value for clinical outcomes.

Cen G, Wu W
Association between tumor necrosis factor-alpha 857C/T polymorphism and gastric cancer: a meta-analysis.
Tumour Biol. 2013; 34(6):3383-8 [PubMed] Related Publications
Tumor necrosis factor-alpha (TNF-α) is an inflammatory cytokine which may play an important role on the immune response may control the progression of gastric cancer. Previous studies on the association between TNF-α 857C/T polymorphism and gastric cancer risk reported conflicting results. We performed a meta-analysis to comprehensively assess the association between TNF-α 857C/T polymorphism and gastric cancer risk. Literature search was performed for all publications on the association between TNF-α 857C/T polymorphism and gastric cancer risk through March 6, 2013. The pooled odds ratios (ORs) with their 95% confidence interval (95%CIs) were calculated to assess the association between TNF-α 857C/T polymorphism and gastric cancer risk. Nine individual case-control studies with a total of 5,054 subjects (1,835 cases and 3,219 controls) were finally included into the meta-analysis. Meta-analysis of total nine studies showed that TNF-α 857C/T polymorphism was significantly associated with increased risk of gastric cancer under four genetic models (for T vs. C: OR = 1.19, 95%CI 1.07-1.33, P = 0.002; for TT vs. CC: OR = 1.44, 95%CI 1.03-2.02, P = 0.032; for CT vs. CC: OR = 1.19, 95%CI 1.05-1.36, P = 0.008; and for TT/CT vs. CC: OR = 1.21, 95%CI 1.07-1.38, P = 0.003). Subgroup analysis by ethnicity further showed that there was a significant association between TNF-α 857C/T polymorphism and increased risk of gastric cancer in Asians but not in Caucasians. The meta-analysis suggests that TNF-α 857C/T polymorphism is significantly associated with increased risk of gastric cancer, especially in Asians.

Wang XX, Cheng Q, Zhang SN, et al.
PAK5-Egr1-MMP2 signaling controls the migration and invasion in breast cancer cell.
Tumour Biol. 2013; 34(5):2721-9 [PubMed] Related Publications
p21-activated kinases (PAKs) are activated by various extracellular stimuli and, in turn, activate other kinases by phosphorylating them at specific serine/threonine residues or through protein-protein interaction. As a recently identified member of the group B PAK family, the role of PAK5 in cancer is poorly understood. In this study, we investigated the effect of PAK5 on the malignant phenotype, such as proliferation, cell cycle, apoptosis, migration, and invasion. Cell growth assay and cell cycle analysis consistently showed that knockdown of PAK5 could significantly inhibit the proliferation of breast cancer cells. Wound healing assay. migration assay, and invasion assay showed that PAK5 promoted cell migration. Furthermore, in order to elucidate the underlying mechanism of PAK5 on cellular growth and migration, we examined the protein expressions of cyclin D1, p21, early growth response protein 1 (Egr1), and matrix metalloproteinase 2 (MMP2). Our work further reveals the PAK5-Egr1-MMP2 signaling pathway to be a critical regulator of cell migration and invasion. These results suggest that PAK5 may be a potential therapeutic target for breast cancer.

Qu Y, Dang S, Hou P
Gene methylation in gastric cancer.
Clin Chim Acta. 2013; 424:53-65 [PubMed] Related Publications
Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field.

Shimwell NJ, Bryan RT, Wei W, et al.
Combined proteome and transcriptome analyses for the discovery of urinary biomarkers for urothelial carcinoma.
Br J Cancer. 2013; 108(9):1854-61 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Proteomic discovery of cancer biomarkers in body fluids is challenging because of their low abundance in a complex background. Altered gene expression in tumours may not reflect protein levels in body fluids. We have tested combining gene expression profiling of tumours with proteomic analysis of cancer cell line secretomes as a strategy to discover urinary biomarkers for bladder cancer.
METHODS: We used shotgun proteomics to identify proteins secreted by three bladder cancer cell lines. Secreted proteins with high mRNA levels in bladder tumours relative to normal urothelium were assayed by ELISA in urine samples from 642 patients.
RESULTS: Midkine and HAI-1 were significantly increased in bladder cancer patients, with the highest levels in invasive disease (area under the receiver operating characteristic curve 0.89 vs non-cancer). The urinary concentration of both proteins was too high to be explained by bladder cancer associated haematuria and most likely arises by direct tumour secretion.
CONCLUSIONS: This 'dual-omic' strategy identified tumour secreted proteins whose urine concentrations are increased significantly by bladder cancer. Combined secretome-transcriptome analysis may be more useful than direct proteomic analysis of body fluids for biomarker discovery in both bladder cancer and other tumour types.

Zhou X, Liu Z, Shi Q, et al.
Geranylgeranyltransferase I regulates HIF-1α promoting glioblastoma cell migration and invasion.
J Neurooncol. 2013; 112(3):365-74 [PubMed] Related Publications
Glioblastoma multiforme is a highly migratory and invasive brain tumor in which hypoxia inducible factor-1α (HIF-1α) plays important roles. However, the underlying mechanisms regulating the action of HIF-1α in glioma cell migration and invasion ability remain unclear. We reported here that HIF-1α was regulated by geranylgeranyltransferase I (GGTI), a protein prenylation transferase, and then promoted glioma cell migration and invasion. The migratory and invasive ability of glioma cells were enhanced by hypoxia treatment but inhibited by down-regulation of HIF-1α. GGTI activity inhibition or GGTI specific β subunit (GGTI β) knocking-down decreased HIF-1α protein level. In addition, down-regulation of GGTI β inhibited migration and invasion of glioma cells under hypoxia, while GGTI β over-expression promoted it. Furthermore, the effect of GGTI β over-expression on cell migration and invasion was abolished by HIF-1α down-regulation. In summary, our study showed, for the first time, that HIF-1α was regulated by protein prenylation transferase GGTI and mediated the effect of GGTI on glioma cell migration and invasion.

Cheng TS, Chen WC, Lin YY, et al.
Curcumin-targeting pericellular serine protease matriptase role in suppression of prostate cancer cell invasion, tumor growth, and metastasis.
Cancer Prev Res (Phila). 2013; 6(5):495-505 [PubMed] Related Publications
Curcumin has been shown to possess potent chemopreventive and antitumor effects on prostate cancer. However, the molecular mechanism involved in curcumin's ability to suppress prostate cancer cell invasion, tumor growth, and metastasis is not yet well understood. In this study, we have shown that curcumin can suppress epidermal growth factor (EGF)- stimulated and heregulin-stimulated PC-3 cell invasion, as well as androgen-induced LNCaP cell invasion. Curcumin treatment significantly resulted in reduced matrix metalloproteinase 9 activity and downregulation of cellular matriptase, a membrane-anchored serine protease with oncogenic roles in tumor formation and invasion. Our data further show that curcumin is able to inhibit the induction effects of androgens and EGF on matriptase activation, as well as to reduce the activated levels of matriptase after its overexpression, thus suggesting that curcumin may interrupt diverse signal pathways to block the protease. Furthermore, the reduction of activated matriptase in cells by curcumin was also partly due to curcumin's effect on promoting the shedding of matriptase into an extracellular environment, but not via altering matriptase gene expression. In addition, curcumin significantly suppressed the invasive ability of prostate cancer cells induced by matriptase overexpression. In xenograft model, curcumin not only inhibits prostate cancer tumor growth and metastasis but also downregulates matriptase activity in vivo. Overall, the data indicate that curcumin exhibits a suppressive effect on prostate cancer cell invasion, tumor growth, and metastasis, at least in part via downregulating matriptase function.

Bose S, Tripathi DM, Sukriti, et al.
Genetic polymorphisms of CYP2E1 and DNA repair genes HOGG1 and XRCC1: association with hepatitis B related advanced liver disease and cancer.
Gene. 2013; 519(2):231-7 [PubMed] Related Publications
A population based case-control study was designed to explore the genetic risk factors for hepatitis B virus (HBV) related liver disease susceptibility. A total of 424 subjects comprising 210 controls, 50 acute HBV (AVH), 84 chronic HBV (CHBV), 25 HBV related cirrhosis and 55 HBV related hepatocellular carcinoma (HCC) cases were included in the study. PCR-RFLP was used for the genotyping of Cyp2E1*5B, hOGG1 codon 326 and XRCC1 codon 399. Compared to controls, Cyp2E1 rsaI variant c2 genotype increased the risk of HBV related liver disease severity by 2.68 fold, the highest for HCC cases (3.981 folds, p=0.106); and was associated with higher histology activity index (HAI) (p<0.001) in CHBV patients. Cyp2E1 and hOGG1 variants were independently associated with a significantly higher fibrosis score in CHBV group. Analysis of gene-gene interaction studies showed an increased risk of HCC, cirrhosis and CHBV in a Cyp2E1 variant+XRCC1 variant combination (p<0.001); and hOGG1 variants+XRCC1 variants. A mutually independent heterozygous hOGG1 and XRCC1 combination resulted in a decreased risk of HBV related liver disease. On the other hand, a wild-type hOGG1 and XRCC1 combination was associated with a significantly higher risk of AVH (p=0.010) but a lower risk of CHBV (p=0.032) and HCC (p=0.006). The gene-gene interactions were also associated with a significant increase in HAI and fibrosis score in CHBV patients. Cyp2E1, hOGG1 and XRCC1 genotypes significantly alter the risk of HBV related liver disease susceptibility and severity, independently or through gene-gene interaction.

Tang LL, Chen FY, Wang H, et al.
Haplotype analysis of eight genes of the monoubiquitinated FANCD2-DNA damage-repair pathway in breast cancer patients.
Cancer Epidemiol. 2013; 37(3):311-7 [PubMed] Related Publications
BACKGROUND: Ten genes are associated with increased susceptibility to inherited breast cancer have also been associated with population breast cancer risk, and all are involved directly or indirectly in the monoubiquitinated FANCD2-DNA damage repair pathway. We analyzed 13 haplotype blocks in eight of these genes to estimate the breast cancer risk conferred by individual haplotypes.
METHODS: Haplotype blocks were constructed with 48 tag single-nucleotide polymorphisms (tSNPs) identified in eight breast cancer susceptibility genes, TP53, PTEN, CHEK2, ATM, NBS1, RAD50, BRIP1, and PALB2. Genotyping was performed by SNPscan on 734 female patients and 672 female age-matched controls.
RESULTS: Forty-five tSNPs were successfully genotyped by SNPscan, and call rates for each tSNP were above 98.9%. Thirteen haplotype blocks of eight genes were constructed with 41 successfully genotyped tSNPs. We found that seven haplotypes from four haplotype blocks located within three genes (NBS1, PTEN, and BRIP1) were significantly associated with breast cancer risk. Among these, four haplotypes (ATC in block 1 of NBS1, GCCCC and GCCCT in block 2 of NBS1, and GCT in block 2 of BRIP1) were correlated with breast cancer risk in sporadic cases (OR (95% CI) 1.350(1.124-1.623), 0.752(0.584-0.969), 0.803(0.649-0.993), and 0.776(0.604-0.997), respectively), and only one haplotype (GGCCT in block 2 of NBS1) was significantly associated with breast cancer risk in familial and early-onset cases (OR(95% CI) 1.902(1.134-3.191)).
CONCLUSIONS: Four haplotypes within two genes (NBS1 and BRIP1) involved in the monoubiquitinated FANCD2-DNA damage-repair pathway are significantly associated with increased sporadic breast cancer risk, while one haplotype within NBS1 is correlated with an increased risk of familial or early-onset breast cancer, indicating that specific haplotypes may be distinct predictors of breast cancer.

Bai ZL, Wang YY, Zhe H, et al.
ERCC1 mRNA levels can predict the response to cisplatin-based concurrent chemoradiotherapy of locally advanced cervical squamous cell carcinoma.
Radiat Oncol. 2012; 7:221 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The purpose of this study was to investigate whether the excision repair cross-complementation group 1 (ERCC1) mRNA expression could predict treatment response of patients with locally advanced cervical squamous cell carcinoma (LACSCC) who underwent cisplatin-based concurrent chemoradiotherapy (CCCRT).
METHODS: A total of sixty LACSCC patients, treated with radical CCCRT from a single institution were evaluated. ERCC1 mRNA expression was determined by quantitative real-time RT-PCR in pre-treatment tumor tissues. The association of ERCC1 status with clinicopathological characteristics (age, histological grade, tumor size, parametrial invasion, lymph node metastasis and FIGO stage) and treatment response were analyzed.
RESULTS: No significant association between ERCC1 mRNA expression and clinicopathological characteristics were observed. Patients with low ERCC1 mRNA level had a significantly higher rate of complete response (86.21%) than patients with high level of ERCC1 expression (19.36%; p < 0.001). In the logistic regression analysis, low ERCC1 mRNA level retained an independent role in predicting complete response to CCCRT (P < 0.001). An ERCC1 expression level of 0.0901 was determined as an optimal cutoff value to identify complete response patients to CCCRT treatment. The sensitivity for detection of a complete response was 81.48% with a specificity of 96.97% (area under the curve, 0.893; 95% confidence interval, 0.804-0.983).
CONCLUSIONS: This is the first analysis of the association between ERCC1 mRNA levels and treatment response in patients with LACSCC. Low ERCC1 mRNA level appears to be a highly specific predictor of response to CCCRT in LACSCC.

Jin G, Reitman ZJ, Duncan CG, et al.
Disruption of wild-type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas.
Cancer Res. 2013; 73(2):496-501 [PubMed] Free Access to Full Article Related Publications
Point mutations at Arg132 of the cytoplasmic NADP(+)-dependent isocitrate dehydrogenase 1 (IDH1) occur frequently in gliomas and result in a gain of function to produce the "oncometabolite" D-2-hydroxyglutarate (D-2HG). The mutated IDH1 allele is usually associated with a wild-type IDH1 allele (heterozygous) in cancer. Here, we identify 2 gliomas that underwent loss of the wild-type IDH1 allele but retained the mutant IDH1 allele following tumor progression from World Health Organization (WHO) grade III anaplastic astrocytomas to WHO grade IV glioblastomas. Intratumoral D-2HG was 14-fold lower in the glioblastomas lacking wild-type IDH1 than in glioblastomas with heterozygous IDH1 mutations. To characterize the contribution of wild-type IDH1 to cancer cell D-2HG production, we established an IDH1-mutated astrocytoma (IMA) cell line from a WHO grade III anaplastic astrocytoma. Disruption of the wild-type IDH1 allele in IMA cells by gene targeting resulted in an 87-fold decrease in cellular D-2HG levels, showing that both wild-type and mutant IDH1 alleles are required for D-2HG production in glioma cells. Expression of wild-type IDH1 was also critical for mutant IDH1-associated D-2HG production in the colorectal cancer cell line HCT116. These insights may aid in the development of therapeutic strategies to target IDH1-mutated cancers.

Zhou X, Qian J, Hua L, et al.
Geranylgeranyltransferase I promotes human glioma cell growth through Rac1 membrane association and activation.
J Mol Neurosci. 2013; 49(1):130-9 [PubMed] Related Publications
Geranylgeranyltransferase I (GGTase-I) is responsible for the posttranslational lipidation of several signaling proteins such as RhoA, Rac1, and Cdc42, which contribute to tumor development and metastasis. However, the role of GGTase-I in the progression of human glioma is largely unknown. Here, we provide the evidence that Rac1 mediates the effects of GGTase-I on the proliferation and apoptosis in human glioma cells. We found that GGTase-I was abundantly expressed in human primary glioma tissues. Inhibition or downregulation of GGTase-I markedly decreased the proliferation of glioma cells and induced their apoptosis, while overexpression of GGTase-I promoted cell growth in vitro. Inactivation of GGTase-I eliminated geranylgeranylation of RhoA and Rac1, prevented them from targeting to the plasma membrane, and inhibited Rac1 activity. Furthermore, overexpressing wild type or constitutively active Rac1 stimulated glioma cell growth, similar to the effect of GGTase-I overexpression. Importantly, overexpressing dominant-negative Rac1 or Rac1 with the prenylation site deleted or mutated abrogated GGTase-I-induced proliferation in glioma cells. These results confirm the view that geranylgeranylation is essential to the activity and localization of Rho family proteins and suggest that Rac1 is required for GGTase-I-mediated glioma growth.

Shangguan L, Ti X, Krause U, et al.
Inhibition of TGF-β/Smad signaling by BAMBI blocks differentiation of human mesenchymal stem cells to carcinoma-associated fibroblasts and abolishes their protumor effects.
Stem Cells. 2012; 30(12):2810-9 [PubMed] Related Publications
Bone marrow mesenchymal stem cells (BM-MSCs) have multiple therapeutic potentials for regenerative, anti-inflammatory, and immunomodulatory purposes and also show promise as vehicles for gene therapy of various metastatic cancers based on their tumor-tropic capacity. However, BM-MSCs are also a source of carcinoma-associated fibroblasts (CAFs) and may promote growth and metastasis of cancer. Transforming growth factor β (TGF-β) signaling is required to induce CAF differentiation of mouse BM-MSCs in vivo and can induce expression of some CAF markers in human BM-MSCs in vitro. To determine whether inhibiting TGF-β signaling in human BM-MSCs can block their differentiation to CAFs induced by tumor microenvironments and the consequent protumor effects, we transduced human BM-MSCs with a lentiviral vector encoding bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), a decoy TGF-β receptor. BAMBI transduction significantly inhibited TGF-β/Smad signaling and expression of CAF markers in human BM-MSCs treated with TGF-β1 or tumor-conditioned medium or cocultured with cancer cells, but did not alter the stem cell properties and the tumor-tropic property of MSCs. In addition, BAMBI transduction disrupted the cytokine network mediating the interaction between MSCs and breast cancer cells. Consequently, BAMBI transduction abolished protumor effects of BM-MSCs in vitro and in an orthotopic breast cancer xenograft model, and instead significantly inhibited growth and metastasis of coinoculated cancer. These results indicated that TGF-β signaling is essential for differentiation of human BM-MSCs to CAFs in tumor microenvironments and the consequent protumor effects, and inhibiting TGF-β/Smad pathway may improve the safety of MSC-based therapies in cancer patients.

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